The role of CD38 within prostate cancer progression must be further explored, along with CD38-targeting in patients with high-risk disease.
CD38-positive prostate tumor-infiltrating immune cells (TIICs) are associated with worse survival outcomes, as well as immunosuppressive mechanisms, providing rationale for further investigation into the role of CD38 within prostate cancer progression and CD38-targeting in patients with high-risk disease, according to data published in European Urology.1
Results showed that in patients with metastatic castration-resistant prostate cancer (mCRPC), CD38 mRNA expression was significantly linked with upregulated immune-signaling pathways, plus interleukin (IL)-12, IL-23, and IL-27 signaling signatures, immunosuppressive adenosine signaling, and T-cell exhaustion signatures.
While CD38 was largely absent from tumor epithelial cells, it was often expressed in phenotypically diverse TIICs, such as B cells and myeloid cells. Moreover, CD38-positive TIIC density was associated with worse overall survival (OS) and increased with progression to castration-resistant prostate cancer (CRPC).
“We believe that CD38 on the surface of immune cells is acting to dampen down the immune response. We have shown that the presence of this protein on immune cells within prostate tumors is a sign of worse survival outcomes and exhausted anticancer immune responses,” said lead study author Johann de Bono, MD, MSc, PhD, FRCP, FMedSci, professor of experimental cancer medicine at The Institute of Cancer Research in London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust.2 “It is now clear that CD38 has a role in prostate cancer’s growth and spread—suggesting that targeting it with drugs, which already exist and are used in other cancers, could be a promising new approach to treatment.”
OS for patients with mCRPC remains poor at 2 to 3 years, and improving outcomes remains dependent on overcoming immunosuppressive barriers in the prostate tumor microenvironment (TME). CD38 upregulation in TIICs has been observed in some gastrointestinal cancers, though not in prostate cancer; however, increasing data have shown evidence that CD38 expression plays and role in tumor immune evasion, and as such, could factor into disease progression in prostate cancer, and serve as an immunotherapeutic target.
In this study, investigators sought to determine the clinical impact of CD38 expression in patients with mCRPC as they progressed to evaluate the potential use of CD38-directed therapies for the treatment of mCRPC.
For this analysis, RNA-sequencing from 159 patients with mCRPC from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) project, as well as 171 samples from 63 patients at the Fred Hutchinson Cancer Research Center, were analyzed for CD38 expression. Samples were then immunohistochemically scored by a validated assay of 51 CRPC biopsies, and matching same-patient castration-sensitive prostate cancer (CSPC) biopsies.
Among these 51 patients, CSPC samples were taken from the prostate (n = 50) and lymph node (n = 1), while CRPC samples were taken from the lymph nodes (n = 30), bone (n = 12), soft tissue (n = 3), liver (n = 3), and prostate (n = 3). mCRPC samples were analyzed for associations between CD38 and other gene expression signatures, while differences in CD38-expressing TIIC densities in the CSPC and CRPC biopsies were evaluated using a negative binomial mixed model. Moreover, multiplex immunofluorescence evaluated CD38 expression.
Results showed that CD38 expression occurred in 35.8% of normal prostatic epithelial cells vs 7.7% of tumor epithelium cells (P < .001). Additionally, the rates of CD38 expression were similar between CSPC and CRPC biopsies, at 9.8% and 3.9%, respectively (P = .45).
In the CSPC samples analyzed, CD38-positive TIIC density was associated with worse OS outcomes from initial diagnosis (HR, 1.36; 95% CI, 1.08-1.70; P = .008). Additionally, high CD38-positive TIIC density, defined as more than 1.5 cells/mm2, was associated with shorter OS from the time of initial diagnosis vs those with low CD38-positive TIIC density (HR, 1.99; 95% CI, 1.09-3.62; P = .02).
Results were similar in the CRPC samples, with CD38-positive TIIC density leading to worse OS outcomes from both the time of biopsy (HR, 1.20; 95% CI, 1.00-1.42; P = .04) and the time of CRPC diagnosis (HR, 1.40; 95% CI, 1.14-1.70; P < .001). Moreover, high CD38-positive TIIC density in these samples was also associated with shorter OS from the time of diagnosis vs low CD38+ TIIC density (HR, 2.24; 95% CI, 1.15-4.00; P = .02).
Additionally, results from a multivariable analysis showed that the CD38-expressing immune cell density seen in CSPC samples lead to worse OS from the time of prostate cancer diagnosis (HR, 1.42; 95% CI, 1.08-1.87; P = .01).
“As cancers develop, they often evolve the ability to evade the immune system so they can keep growing and spreading without being attacked. This new study suggests that in prostate cancer, tumors can suppress the immune system via the CD38 molecule on the surface of immune cells,” said Paul Workman, FRS, FRSC, FMedSci, chief executive of The Institute of Cancer Research in London. “The findings are exciting and open up a whole new potential approach to treating prostate cancer using immunotherapy—an approach that is now being tested in clinical trials which have the potential to show real benefit for patients.”